Following Eisenmenger’s initial description in 1897Reference Eisenmenger1 of a 32 year old man with cyanosis and hemoptysis who was found after death to have a large ventricular septal defect, it was Paul Wood in 1958Reference Wood2 who coined the term Eisenmenger syndrome to describe situations where high pulmonary blood flow due to a left-to-right shunt results in pulmonary vascular occlusive disease and reversal of the shunt across the defect. This session provides a broad outline of the disease and attempts to examine some of the questions that relate to diagnosis and management of this syndrome, recognizing that there is considerable paucity of studies that have been specifically designed to address them.
Definition
The Eisenmenger syndrome represents an advanced stage of a spectrum of structural and functional changes in the pulmonary vasculature which lead to a progressive increase in pulmonary vascular resistance. To most clinicians, the term “Eisenmenger syndrome” also includes patients who never presented with increased pulmonary flow (advanced pulmonary vascular disease early in life) and those with cyanotic congenital cardiac defects (for example, transposition of the great arteries) associated with exceedingly high pulmonary vascular resistance. An updated definition that represents a consensus among experts needs to be developed.
While it is now seldom seen in industrialized nations, the Eisenmenger syndrome continues to be common in most developing countries where infant cardiac surgery is largely unavailable to the average child with congenital cardiac disease. In these parts of the world, it constitutes a sizable fraction of a large population of unoperated patients with congenital cardiac defects. Until recently, the absence of specific treatment options for pulmonary vascular disease associated with congenital cardiac defects resulted in varying degrees of therapeutic nihilism and little structured management was offered, particularly in developing countries. Fortunately, the prognosis is far better than in most other forms of pulmonary arterial hypertension including the idiopathic form. Apart from newer medications, a number of measures can be undertaken to allow patients with pulmonary hypertension associated with congenital cardiac disease to lead reasonably productive lives with perhaps improved longevity.
Current knowledge
All congenital cardiac defects with an increased pulmonary blood flow have a propensity to develop pulmonary vascular disease.Reference Granton and Rabinovitch3 The likelihood and rate of development of vascular abnormalities is determined by a number of variables that include the quantum of left to right shunt, the nature of the underlying defect and duration of exposure of the pulmonary vascular bed to increased flow. Left-to-right shunts at the level of ventricles or great arteries (post-tricuspid) have a greater chance of developing pulmonary vasculopathy as compared to shunts at atrial level (pre-tricuspid). Cyanotic cardiac defects with increased pulmonary blood flow (e.g. transposition of the great arteries with ventricular septal defect or patent arterial duct, persistent truncus arteriosus) are particularly likely to develop early vasculopathy, often during infancy.
A number of additional variables appear to operate but are poorly understood. The response of the pulmonary vasculature to a high pulmonary blood flow is not uniform from patient to patient and does not occur in a predictable fashion. There appears to be a spectrum in the development of pulmonary vascular disease with a subset of patients with a high pulmonary vascular resistance and advanced pulmonary vascular occlusive lesions in early infancy at one side, and adults who remain operable with large left-to-right shunts at the other. Conditions such as Trisomy 21, thoracic and spinal skeletal deformities, and lung parenchymal disease are often associated with a higher likelihood of developing pulmonary vascular disease.
Exposure to high blood flow results in impaired endothelium mediated relaxation and increased vasomotor tone accompanied by histological changes in the vessel wall.Reference Granton and Rabinovitch3–Reference Diller and Gatzoulis5 The histological changes include extension of smooth muscles into peripheral pulmonary arteries, medial hypertrophy, reduction of total cross-sectional area of the peripheral pulmonary arterial tree and formation of dilated lesions, as for example, the so-called plexiform lesions. Loss of endothelial barrier function resulting from high flow and pressure, activation of the endothelin system, decreased production of prostacyclin, decreased production of nitric oxide, increased turnover of serotonin, and altered expression of potassium channels have all been implicated in the pathobiology of vascular remodeling in pulmonary arterial hypertension in general, and are likely to occur in congenital cardiac disease.Reference Granton and Rabinovitch3–Reference Diller and Gatzoulis5
Clinical evaluation
The Eisenmenger syndrome should be viewed as a multisystem disease.Reference Perloff, Rosove, Sietsema and Territo6 Multiple organ systems are affected as a result of chronic hypoxia, erythrocytosis and, heart failure (Table 1). Infectious complications such as endocarditis and brain abscess are common. Diagnostic evaluation should therefore be comprehensive.
Clinical features in the Eisenmenger syndrome.
The commonest symptom is exercise intolerance. Other common symptoms include dyspnea, syncope, chest pain, cyanosis and, hemoptysis. Pulmonary hypertension is readily evident on physical examination in the form of a loud pulmonary component of the second heart sound, prominent pulmonary arterial pulsations, right ventricular heave and, in many instances, an early diastolic murmur of pulmonary regurgitation. Additional murmurs of tricuspid regurgitation may be present but the murmur across the primary cardiac defect disappears.
Central cyanosis is usually readily identifiable and often accompanied by clubbing. It may be limited to the lower limbs in patent ductus arteriosus with shunt reversal, or only apparent through measurement of oxygen saturation. This can happen in presence of significant anemia or if the nail beds are pigmented.
Diagnosis and testing
The investigations that need to be ordered are dictated to some degree by the presenting manifestations and available resources. For the average “uncomplicated” patients presenting at a tertiary care center, the purpose of investigations includes the following:
1. To confirm the diagnosis of severe pulmonary hypertension
2. To correctly characterize the underlying heart lesions
3. To exclude any potentially reversible cause for elevation of pulmonary vascular resistance and other causes of hypoxia
4. To evaluate the extent of multi-organ dysfunction
5. To obtain an objective estimate of the baseline functional status.
Investigations need to be chosen judiciously in limited resource environments. Although most of the investigations (Table 2) provide useful information, they sometimes have only a limited impact on treatment choices and patient well-being.
Suggested diagnostic approach to patients with suspected Eisenmenger syndrome.
Treatment
Recognizing the fact that multiple organ systems are deranged in most patients with Eisenmenger syndrome, these patients should be managed in a facility where a multidisciplinary approach is feasible. Specialized clinics conducted by cardiologists with expertise in adult congenital cardiac disease are ideally suited for them. Consultations with cardiac electrophysiology, obstetrics and gynecology, nephrology, pulmonology, hematology, neurology, orthopedics and gastroenterology are required in many patients. For female patients, advice about contraception is essential. The clinic should be supported by a comprehensive hematology and biochemistry laboratory and imaging services. Dedicated paramedical staff including medical social workers and specialized nursing staff are necessary to provide support and counsel them on a number of specific issues. Appropriate educational material with information on common questions relating to the disease should be prepared and made available to all patients.
Life style
Limitation in exercise tolerance is invariable in patients with the Eisenmenger syndrome, and risk of dehydration is substantial especially in tropical climates. Occupations that require frequent traveling or long commutes are perhaps best avoided. Many patients are able to lead reasonably productive and independent lives pursuing occupations that involve minimal physical stress. Activities and occupation are largely directed by the patients themselves and therefore education and counseling is particularly important. Air travel can be undertaken but dehydration associated with long flights should be prevented through generous intake of fluids.Reference Broberg, Uebing, Cuomo, Thein, Papdopoulous and Gatzoulis7 Acute exposures to altitudes in excess of 2500 meters should be avoided.Reference Penalosa and Arias-Stella8 Endocarditis prophylaxis and meticulous attention to oral-dental hygiene is mandatory. Annual immunization against influenza and pneumococcal infections may be considered in regions where these infections are prevalent.
Pregnancy and contraception
Pregnancy is associated with a substantial risk of maternal and fetal mortality.Reference Diller and Gatzoulis5, Reference Yentis, Steer and Plaat9 The risks of pregnancy should be explained to women with the Eisenmenger syndrome as soon as the diagnosis is confirmed. The options for contraception include progestogen impregnated intrauterine coils and subdermal progesterone implant. Standard oral estrogen contraceptive pills are associated with risk of thrombosis and laparoscopic sterilization carries the risk of general anesthesia. In the event the patient becomes pregnant and does not wish termination, an obstetrician and anesthesiologist should be consulted and the patient should be carefully monitored during pregnancy, at the time of delivery and 1–2 weeks post-partum when the risk of death is at its highest.
Non cardiac surgery
Non-cardiac surgery carries a substantial additional risk. There are no specific protocols for anesthesia recommended for patients with Eisenmenger syndrome. Careful attention to detail and close monitoring throughout the surgery and in the early postoperative period is necessary. The anesthesiologist should be involved whenever surgery is planned and the specific physiologic derangements associated with the underlying cardiac condition should be explained. Inhalational agents are associated with reduction in systemic vascular resistance and therefore an increase in right-to-left shunt with further decline in saturation can be expected.Reference Lovell10 Additional issues include the risk of bleeding and rapid changes in intravascular volume.
Secondary erythrocytosis: phlebotomy
Routine phlebotomy often worsens iron deficiency and is associated with an increased risk of strokeReference Perloff, Marelli and Miner11, Reference Perloff, Rosove, Child and Wright12 and further reduction in exercise tolerance.Reference Broberg, Bax and Okonko13 Compensated secondary erythrocytosis is often well tolerated.Reference Perloff, Rosove, Child and Wright12 Even hematocrit levels around 65% are well tolerated in many patients. For reasons that are not clear, it is often difficult to stop doing serial phlebotomies once they are started. Therefore, hemodilution should be indicated strictly to relieve hyperviscosity-related symptoms such as blurry vision, headaches, dizziness, arthralgia and worsening of dyspnea. In all instances, maintaining an iron-replete state is crucial.
Anticoagulant therapy
Although there is no clear evidence supporting the benefit of chronic anticoagulation in the specific setting of the Eisenmenger syndrome, previous studies point toward a tendency to the development of extensive pulmonary arterial thrombosis.Reference Broberg, Ujita and Babu-Narayan14, Reference Broberg, Ujita and Prasad15 On the other hand, most specialists would agree that these patients are at risk for bleeding episodes. Therefore, anticoagulation should not be considered if serious monitoring is not possible for any reasons. In this way, special blood tubes are needed to measure the prothrombin time in the presence of an elevated hematocrit.
Oxygen therapy
The long-term effects of oxygen therapy still need to be confirmed. Improved survival has been reported in a small group of children with pulmonary vascular disease receiving long-term oxygen therapy.Reference Bowyer, Busst, Denison and Shinebourne16 Long-term nocturnal oxygen therapy, however, does not improve symptoms, exercise capacity, and outcome in adult patients with Eisenmenger syndrome.Reference Sandoval, Aguirre and Pulido17
Emerging pharmacologic interventions
A number of newer agents promise to change the outlook of patients with the Eisenmenger syndrome. These agents target the pulmonary vasculature with a relatively high degree of selectivity. Data on their use in congenital cardiac disease with advanced pulmonary vasculopathy are still quite preliminary, and large trials are awaited. In terms of drugs that can be administered orally, agents have been specifically developed for endothelin receptor antagonism and phosphodiesterase-5 inhibition.Reference Galie, Beghetti and Gatzoulis18–Reference Mukhopadhyay, Sharma and Ramakrishnan21 Details regarding the mechanism of action, published evidence and recommendations for the use of these drugs, as well as the prostanoids, will be discussed in a specific chapter. Most importantly, patients with the Eisenmenger syndrome have a relatively favorable natural history as compared for example with idiopathic pulmonary hypertension, with much better survival curves.Reference Diller, Dimopoulos and Broberg22, Reference Hopkins, Ochoa, Richardson and Trulock23 Thus, the short-term benefits that have been observed in terms of exercise endurance and hemodynamics may not be predictive of long-term improvement of outcomes. In this way, years of follow-up are needed before survival benefits can be demonstrated.
In the only prospective and controlled study published so far in the specific setting of the Eisenmenger syndrome, bosentan improved exercise endurance at 16 weeks, without any deleterious effects on gas exchange.Reference Galie, Beghetti and Gatzoulis18 Studies that enroll patients with class III and IV symptoms are likely to yield results over a relatively shorter duration of follow-up in view of the substantially poor prognosis in this group. In a retrospective analysis of 43 patients in an institutional registry (many in Class II), no survival advantage could be demonstrated among those who received the newer therapies in comparison with those who remained on standard care.Reference Adriaenssens, Delcroix, Van Deyk and Budts24
The availability of the so called “new therapies” for pulmonary hypertension led many physicians to become more aggressive in terms of assigning patients to closure of the defects. It should be emphasized, however, that there are no long-term studies on the efficacy of these drugs, and patients may deteriorate more rapidly than if they had never been operated on. Thus, in terms of operation, “benign neglect” is often preferable.
Conclusions
Several areas may be worth pursuing potentially to improve the outlook for patients with pulmonary hypertension associated with congenital cardiac disease. The basis of extraordinary individual variability in the tendency to develop severe pulmonary vasculopathy needs to be thoroughly investigated. Likewise, the remarkable performance of the right ventricle deserves further research. These investigations would improve our understanding and may allow development of additional specific strategies for treatment. Besides, large randomized controlled trials are needed in the specific setting of the Eisenmenger syndrome for a better understanding of the impact of newer therapies (either alone or in combination) on the long-term outcomes. Ideally, these trials should consider the inclusion of hard endpoints such as long-term survival, and compare conventional and new treatments in patients with the same type of intracardiac abnormality.
